Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. While current therapy is effective for the majority of children, relapsed ALL remains the fifth most common pediatric malignancy and responds very poorly to treatment. In addition, 30% of ALL cases occur in adults, and while remission is achieved in many patients the majority of these will succumb to relapsed disease. In most cases relapse is treated with more intensive chemotherapy or hematopoietic cell transplantation (HCT), therapies that are associated with significant toxicities. In both patient populations, therefore, there is an urgent need for novel approaches to inhibit disease progression. We have recently evaluated the ability of immunostimulatory DNA (CpG ODN) to induce immune activity against primary human ALL cells in vivo, using NOD-SCID mice. Repeated administration of CpG ODN into mice with established disease led to continued disease control and significantly improved survival. Based on these exciting results, we hypothesize that CpG ODN will have considerable potential as a novel agent for the chemoprevention of ALL progression. In this application we will perform further critical preclinical analysis of these agents, to evaluate their ability to induce immune- mediated killing of a broad panel of ALL sub-types, to prevent disease recurrence after chemotherapy, and to induce killing of autologous ALL blasts. We believe that the successful completion of this application will provide a solid basis for the use of CpG ODN as a novel adjuvant chemotherapy agent for the prevention of ALL recurrence in successfully treated patients. While the majority of patients with acute lymphoblastic leukemia respond well to initial therapy and achieve complete remission, a significant proportion subsequently relapse and for these patients treatment options are limited. The design of new therapies that would complement chemotherapy may significantly reduce the rate of relapse for this disease. This application will investigate the potential of novel immune modulators to reduce ALL relapse after treatment with chemotherapy. [unreadable] [unreadable] [unreadable]